Immune complexes play a central role in the recruitment of neutrophils and mononuclear phagocytes which is critical in the development of tissue injury in vasculitis. While the in vivo process of vascular injury is no doubt complex, new insights int=o the molecular and cell biology of phagocytes, into the structural genetics and function f Fcgamma receptors which interact with immune complexes characteristic of cutaneous necrotizing vasculitis, and into the cell programs initiated by these receptors have brought critical new areas of research into clear focus. We believe these new areas provide an unprecedented opportunity to define genetic risk factors for disease predisposition nd to develop targeted therapeutic strategies. There are multiple cell triggers for neutrophil activation, but of particular relevance to the vasculitides characterized b immune complexes is the recognition of the complexity of human Fcgamma receptors. Human Fcgamma receptors consist of three families, each with multiple genes, alternative splice variants and allelic polymorphisms which are functionally distinct. For example, the Fcgamma RIIA LR allele (which is expressed on neutrophils and mononuclear phagocytes) is the only human Fcgamma receptor which recognizes human IgG2 efficiently, -- thus establishing the precedent for interaction between the qualitative and quantitative nature of the humoral immune response and defined Fcgamma receptor genotypes. Fcgamma receptors on phagocytes are effective triggers for cell programs important for cell adhesion and inflammatory tissue lesions. These observations are important because they provide (1) a genetic basis for individual difference in patient responses in vasculitis, and (2) a framework for understanding how the properties of autoantibodies interplay with Fcgamma receptors on phagocytes to lead to tissue damage. Therefore, we hypothesize (1) that autoantibodies bind Fcgamma receptors and trigger phagocytes, and (2) that Fcgamma receptor-mediated triggering is important in initiating cell functions including homo- and heterotypic adhesion, synthesis and release of cytokines (IL01 1L-8, IFNalpha), and release of both granular enzymes and short-lived inflammatory mediators (reactive oxygen intermediates). Furthermore, we hypothesize (1) that subjects with the FcgammaRIIA lr (Fcgamma RIIA-H131) allele capable of binding huIgG2 efficiently will be a higher risk for development of disease as will (2) subjects with the FcgammaRIIIB NA1 allele which is functionally more active than its reciprocal NA2 allele.